Dr. Binder's goal is to become a leading academic epidemiologist in the epigenetic programming of health and disease, with an emphasis on hormonally responsive cancer risk. She plans to apply innovative methodological approaches to efficiently capture biologically meaningful changes in gene regulation. Dr. Binder will collaborate with a broad spectrum of scientists to translate insight from these mechanistic studies into improvements in health care and disease prevention. Her research thus far has focused on determinants of epigenetic patterns established in utero and during puberty. The proposed research project will bridge this experience to study the impact of epigenetic modifications acquired across the life course on postmenopausal breast cancer incidence. Epigenetic age is a predictor of health and an indicator of biological aging, capturing the cumulative impact of environmental and behavioral influences across time on cellular function. Prior studies have suggested a positive correlation between epigenetic aging and cancer risk. Paradoxically, aspects of reproductive history suggested to decelerate epigenetic age are associated with increased breast cancer incidence. Therefore we hypothesize there is a clinically relevant interaction between epigenetic age and the process of reproductive aging on hormonally responsive cancer risk among postmenopausal women. We propose analyzing epigenetic age acceleration (AgeAccel; deviance between chronological and epigenetic age) within 5,406 postmenopausal women from the Women's Health Initiative Observational Study and Clinical Trial with previously measured genome-wide DNA methylation in whole blood. This will include a subset of 1,382 women with bioavailable estradiol measurements, and 285 cases of invasive breast cancer. We plan to (1) characterize the variation in AgeAccel associated with reproductive history, (2) assess how AgeAccel is influenced by lifestyle factors, (3) analyze the association between AgeAccel and bioavailable estradiol and testosterone, (4) investigate how these hormones may mediate and interact with modifiable and unmodifiable predictors of cancer risk to impact AgeAccel, and (5) estimate the association between AgeAccel and breast cancer hazard. Together these aims will separate the influences on biological aging from chronological age relevant for cancers associated with reproductive history among postmenopausal women. Additionally, this work will appraise the utility of AgeAccel to track the change in risk profile over time. To conduct this research, Dr. Binder will build her substantive knowledge of aging and postmenopausal health through organized mentorships, didactic coursework, affiliations with interdisciplinary research institutes and associated seminars. Furthermore, Dr. Binder will generate new research partnerships with experts in cancer control and prevention to inform her analytic approach and interpretations. This development plan will build Dr. Binder's reputation in the epigenetic programming of women's health and cancer risk through publications and presentations, increase her network of collaborators, and fuel the submission of a research grant to further her career as an independent investigator in this field.